DESCRIPTION (Adapted from the application): The objective of this project is to develop gene therapy for treating AD. The recent development of mice that express genes involved in AD has provided animal models in which the development of neuropathology can be studied experimentally. Senile plaques, intricately organized, complex structural malformations that are hallmarks of AD neuropathology, may develop from diffuse extracellular deposits of beta amyloid (AB). Two genes that are genetically linked to early-onset familial AD subtypes, amyloid precursor protein (APP) and presenilin 1 (PS1), can also influence AB deposition in mice made transgenic for these genes. Although senile plaques do not form in mice transgenic for either APP or PSI singly, and other features of AD are absent, behavioral and neuropathological analyses suggest that transgenic mice expressing certain variants of these genes do have many similarities to early AD. Mice transgenic for both APP and PSI variants associated with familial AD, however, exhibit dramatically enhanced AB deposition that begins early in life. The applicants intend to use such transgenic mice as a starting point for manipulating the phenotype towards or away from human AD, and as a model for developing gene therapy that will work in brains containing abnormal AB deposits (e.g., AD patients). Vectors for persistent gene transfer based on modified adeno-associated virus (AAV) will be used to induce neurons to express selected genes in situ in the brains of mature transgenic and normal mice. Superoxide dismutase 1 (SOD1) and bc1-2 genes will be delivered to test their ability to protect basal forebrain cholinergic neurons that lose their neurotransmitter phenotype and can die when they are deprived of neurotrophic factor support by experimental disconnection from their synaptic targets. This experimental model has analogies with AD, and may be aggravated by APP or PSI dysfunction in the transgenic mice. They will also test rAAV gene delivery as a potential means to reduce AB deposition in APP/PS transgenic mice by introducing genes for clusterin (ApoJ) and apolipoprotein E3. Such an effect could reduce the progress and/or severity of AD. In contrast, interleukin-6 (IL-6) and tau, genes will be delivered in other experiments aimed at recruiting inflammatory/immune and neurofibrillary components of AD pathology, which are essentially absent from the transgenic mice. These are predicted to make the histopathology in APP/PS1 tranegenic mice even more like that observed in AD.